rs782321294

chrX-154365224-C-AchrX-154365224-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001110556.2(FLNA):c.1603G>T(p.Asp535Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D535N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: FLNA NM_001110556.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.56

Genes affected

FLNA (HGNC:3754): (filamin A) The protein encoded by this gene is an actin-binding protein that crosslinks actin filaments and links actin filaments to membrane glycoproteins. The encoded protein is involved in remodeling the cytoskeleton to effect changes in cell shape and migration. This protein interacts with integrins, transmembrane receptor complexes, and second messengers. Defects in this gene are a cause of several syndromes, including periventricular nodular heterotopias (PVNH1, PVNH4), otopalatodigital syndromes (OPD1, OPD2), frontometaphyseal dysplasia (FMD), Melnick-Needles syndrome (MNS), and X-linked congenital idiopathic intestinal pseudoobstruction (CIIPX). Two transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FLNA
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLNA	NM_001110556.2	c.1603G>T	p.Asp535Tyr	missense_variant	11/48	ENST00000369850.10
FLNA	NM_001456.4	c.1603G>T	p.Asp535Tyr	missense_variant	11/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLNA	ENST00000369850.10	c.1603G>T	p.Asp535Tyr	missense_variant	11/48	1	NM_001110556.2

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000827 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	24
Dann	Benign	0.92
DEOGEN2	Pathogenic	0.88	D;.;.;.;.
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;.;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;H;H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-7.2	D;.;D;D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.99	D;.;B;B;.
Vest4		0.72
MutPred		0.67		Gain of phosphorylation at D535 (P = 0.0117);.;Gain of phosphorylation at D535 (P = 0.0117);Gain of phosphorylation at D535 (P = 0.0117);.;
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782321294; hg19: chrX-153593592;